Transdermal testosterone device and delivery

ABSTRACT

Described are transdermal drug delivery systems for the transdermal administration of testosterone, comprising a polymer matrix and testosterone. Methods of making and using such systems also are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. 61/265,411, filed Dec. 1, 2009,the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

Described herein are compositions and methods for the transdermaldelivery of testosterone.

BACKGROUND

This invention relates generally to transdermal drug delivery systems,and more particularly, to transdermal drug delivery systems for thedelivery of testosterone. The use of a transdermal system, for example,a patch comprising a pressure-sensitive adhesive containing a drug, as ameans of delivering drug through the skin is well known. However, thereremains a need for transdermal drug delivery systems designed for thedelivery of specific drugs, such as testosterone, and there remains aparticular need for smaller transdermal drug delivery systems thatexhibit desired pharmacokinetic properties.

Transdermal delivery systems (adhesive patches) as dosage forms havebeen the subject of a vast number of patent applications over the last25 years, yielding many patents but few commercial products incomparison. To those working in the field, the relatively small numberof commercial products is not surprising. Although regulatory, economic,and market hurdles play a role in limiting the number of products on themarket, the task of developing a transdermal delivery system thatachieves desired physical and pharmacokinetic parameters to satisfyphysician and patient demand is more daunting. Parameters to beconsidered during commercial product development may include drugsolubility, drug stability (e.g., as may arise from interaction withother component materials and/or the environment), delivery of atherapeutic amount of drug at a desired delivery rate over the intendedduration of use, adequate adhesion at the anatomical site ofapplication, integrity (e.g., minimal curling, wrinkling, delaminatingand slippage) with minimal discomfort, irritation and sensitization bothduring use and during and after removal, and minimal residual adhesive(or other components) after removal. Size also may be important from amanufacturing and patient viewpoint, and appearance may be importantfrom a patient viewpoint. The physical manufacturing and productionaspects of commercial product development (e.g., the identity and costsof materials, equipment, and labor) and supporting analytical methodsrequired for regulatory compliance also can be significant.

Of the physical parameters that are considered when developing acommercial transdermal drug delivery system, size, e.g., surface area atthe site of application, is often dictated and limited by other physicaland pharmacokinetic requirements, such as desired drug delivery ratesand daily dosages. In general, it is easier to develop a relatively“large” transdermal drug delivery system that will achieve drug deliveryat target therapeutic levels over an intended duration of therapy, thanit is to develop a smaller transdermal drug delivery system that stillexhibits acceptable pharmacokinetic properties. Still, because sizedirectly impacts costs (e.g., costs of component materials, costs ofpackaging materials, costs for production and manufacturing equipment,labor costs relative to product yield per run time, etc.) and patientsgenerally prefer smaller systems to larger ones (both for aestheticreasons and comfort, since a smaller surface may permit the use of lessaggressive adhesives), there is a need for smaller transdermal drugdelivery systems.

SUMMARY

In accordance with one embodiment, there is provided a transdermal drugdelivery system comprising a drug containing layer defining an activesurface area and comprising a polymer matrix comprising testosterone,wherein the system includes less than 0.3 mg/cm² testosterone andachieves a testosterone flux that is at least about 0.7 μg/cm²/hour,such as at least about 0.89 μg/cm²/hour, based on the active surfacearea. In some embodiments, the polymer matrix comprises a polymer blendcomprising an acrylic adhesive, a silicone adhesive, and soluble PVP. Insome embodiments, the polymer matrix comprises about 2-25% by weightacrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25%by weight soluble PVP, about 0-15% penetration enhancer, about 0.1-10%by weight testosterone, and, optionally, about 0.001-0.1% by weightantioxidant, all based on the total dry weight of the polymer matrix. Insome embodiments, the polymer matrix comprises about 20% by weightacrylic adhesive, about 59% by weight silicone adhesive, about 12% byweight soluble PVP, about 6.0% by weight oleyl alcohol, about 2-3% byweight testosterone, and, optionally about 0.01% by weightbutylhydroxytoluene, all based on the total dry weight of the polymermatrix. In some embodiments, the acrylic adhesive and silicone adhesiveare present in a ratio of from about 1:2 to about 1:6, based on thetotal weight of the acrylic and silicone adhesives.

In some embodiments, the penetration enhancer comprises oleyl alcohol ordipropylene glycol, or both.

In some embodiments, the polymer matrix comprises an amount oftestosterone effective to deliver a therapeutically effective amount oftestosterone over a period of time selected from the group consisting ofat least 1 day, at least 2 days, at least 3 days, at least 4 days, atleast 5 days, at least 6 days and at least 7 days. In some embodiments,the polymer matrix comprises an amount of testosterone effective todeliver an amount of testosterone of at least 300 μg/day, over a periodof at least 3 days.

In some embodiments, the polymer matrix has a coat weight of greaterthan about 10 mg/cm². In some embodiments, the polymer matrix has a coatweight selected from the group consisting of about 12.0, about 12.5,about 13.0 and about 15 mg/cm².

In accordance with some embodiments, there is provided a transdermaldrug delivery system comprising a polymer matrix comprisingtestosterone, wherein the system has an active surface area that isabout 50% of 28.0 cm², including about 14 cm², and is effective todeliver an amount of testosterone per day of at least 300 μg/day.

In accordance with some embodiments, there is provided a method foradministering testosterone, comprising applying to the skin or mucosa ofa subject in need thereof a transdermal drug delivery system comprisinga drug-containing layer defining an active surface area and comprising apolymer matrix comprising testosterone, wherein the system includes lessthan 0.3 mg/cm² testosterone and achieves an testosterone flux that isat least about 0.7 μg/cm²/hour, such as at least about 0.89 μg/cm²/hour,based on the active surface area. In some embodiments, the system has anactive surface area that is about 50% of 28.0 cm², including about 14cm², and is effective to deliver an amount of testosterone per day of atleast 300 μg/day.

In accordance with some embodiments, there is provided a method ofmaking a transdermal drug delivery system for administeringtestosterone, comprising forming a polymer matrix comprisingtestosterone and a polymer blend comprising an acrylic adhesive, asilicone adhesive, and soluble PVP, and applying the polymer matrix to asupport layer such that the system includes less than 0.3 mg/cm²testosterone. In some embodiments, the system has an active surface areathat is about 50% of 28.0 cm², including about 14 cm². In someembodiments, the polymer matrix comprises about 20% by weight acrylicadhesive, about 59% by weight silicone adhesive, about 12% by weightsoluble PVP, about 6.0% by weight oleyl alcohol, about 2-3% by weighttestosterone and, optionally about 0.01% by weight butylhydroxytoluene,all based on the total dry weight of the polymer matrix. In someembodiments, the polymer matrix is applied to the support layer at acoat weight of greater than about 10 mg/cm². In some embodiments, thepolymer matrix coat weight is selected from the group consisting of12.0, about 12.5, about 13.0 and about 15 mg/cm².

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the testosterone flux (μg/cm²/hr) over time (0-96hours) from a transdermal delivery system according to the invention(), as compared to Intrinsa® (♦).

FIG. 2 illustrates the cumulative amount of drug delivered per unit area(μg/cm²) over time (0-96 hours) from a transdermal delivery systemaccording to the invention (), as compared to Intrinsa® (♦).

DETAILED DESCRIPTION

The field of transdermal delivery systems suffers from the problem ofneeding to balance many different competing factors to develop acommercial product that exhibits, for example both clinical efficacy andsatisfactory wear properties while remaining acceptable to patients. Forexample, when selecting the size of a transdermal delivery system, it isnecessary to balance factors that favor a smaller size (such as lowercost, better adhesive performance and improved aesthetics) againstfactors that favor a larger size (such as the target delivery rate(flux) and daily dose). The Intrinsa® transdermal testosterone product(manufactured by Watson Pharmaceuticals Inc.) is 28 cm² and contains 8.4mg of testosterone. Thus, the Intrinsa® product includes 0.3 mg/cm²testosterone. The Intrinsa® product is said to deliver 300 μgtestosterone per day.

In accordance with some embodiments, the present invention providestransdermal drug delivery systems for the transdermal delivery oftestosterone that have a smaller active surface area than Intrinsa® butachieve daily dosages that are about equal to or greater than theIntrinsa® products. For example, the present invention includestransdermal drug delivery systems that achieve daily dosages that areabout equal to an Intrinsa® product, in a smaller sized system. Theability to provide a smaller system without sacrificing daily dosagerepresents a significant advance.

Applicant surprisingly discovered that adjusting the coat weight of thedrug-containing adhesive layer could be used to adjust the flux per unitarea, and thus permitted the development of smaller transdermal drugdelivery systems that achieve comparable daily dosages. This result issurprising because coat weight is typically selected to control theduration of delivery, but is not generally understood to impact deliveryrate. Thus, while it is known in the art to increase coat weight toprovide delivery over a longer period of time, it was not known thatincreasing coat weight could increase delivery rate or flux, and thuspermit the development of a smaller system while maintaining dailydosage.

Moreover, Applicant surprisingly discovered that the drug-containingadhesive layers described herein achieve a flux per unit area that isgreater than that of the Intrinsa® product, but with a similar amountdrug per unit area. This permitted the development of smallertransdermal drug delivery systems that achieve comparable daily dosages.This result is surprising because Applicant is able to achievecomparable drug delivery with less drug.

In accordance with some aspects, there are provided transdermal drugdelivery systems and methods for the transdermal delivery oftestosterone. In specific embodiments, the systems exhibit increasedflux than other known testosterone devices (such as Intrinsa®,manufactured by Watson Pharmaceuticals Inc.) and, therefore, exhibitincreased drug delivery per unit area. For example, in some embodiments,the systems exhibit a flux greater than the about 0.45 μg/cm²/hourexhibited by the Intrinsa® product, such as a flux that is at leastabout 0.70 μg/cm²/hour, including a flux that is at least 0.70μg/cm²/hour, including a flux that is at least about 0.89 μg/cm²/hour,at least 0.89 μg/cm²/hour, at least about 1.0 μg/cm²/hour, at least 1.0μg/cm²/hour, at least about 1.5 μg/cm²/hour, and at least 1.5μg/cm²/hour. In some embodiments, the systems described herein achieve aflux that at least is about 0.70 μg/cm²/hour, including at least 0.70μg/cm²/hour, at least about 0.89 μg/cm²/hour, at least 0.89 μg/cm²/hour,at least about 1.0 μg/cm²/hour, at least 1.0 μg/cm²/hour, at least about1.5 μg/cm²/hour, or at least 1.5 μg/cm²/hour, over a period of time of aleast 3 days, including a period of time of 3 days, or a period of timeof 4 days or longer.

In some embodiments, the systems have a lower amount of drug per unitarea than other known testosterone devices, but still achieve effectivedrug delivery. For example, in some embodiments, the systems have a coatweight such that the amount of testosterone per unit area is less thanthe 0.3 mg/cm² testosterone of the Intrinsa® product, such as an amountof drug per unit area of about 0.28 mg/cm².

Thus, in accordance with some aspects, the invention permits the use ofsmaller devices to achieve comparable drug delivery.

DEFINITIONS

Technical and scientific terms used herein have the meanings commonlyunderstood by one of ordinary skill in the art to which the presentinvention pertains, unless otherwise defined. Reference is made hereinto various methodologies known to those of ordinary skill in the art.Publications and other materials setting forth such known methodologiesto which reference is made are incorporated herein by reference in theirentireties as though set forth in full. Any suitable materials and/ormethods known to those of ordinary skill in the art can be utilized incarrying out the present invention. However, specific materials andmethods are described. Materials, reagents and the like to whichreference is made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

As used herein, the singular forms “a,” “an,” and “the” designate boththe singular and the plural, unless expressly stated to designate thesingular only.

The term “about” and the use of ranges in general, whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range while not departing fromthe scope of the invention. As used herein, “about” will be understoodby persons of ordinary skill in the art and will vary to some extent onthe context in which it is used. If there are uses of the term which arenot clear to persons of ordinary skill in the art given the context inwhich it is used, “about” will mean up to plus or minus 10% of theparticular term.

The phrase “substantially free” as used herein generally means that thedescribed composition (e.g., transdermal drug delivery system, polymermatrix, etc.) comprises less than about 5%, less than about 3%, or lessthan about 1% by weight, based on the total weight of the composition atissue, of the excluded component.

As used herein “subject” denotes any animal in need of drug therapy,including humans. For example, a subject may be suffering from or atrisk of developing a condition that can be treated or prevented withtestosterone, or may be taking testosterone for health maintenancepurposes.

As used herein, the phrases “therapeutically effective amount” and“therapeutic level” mean that drug dosage or plasma concentration in asubject, respectively, that provides the specific pharmacologicalresponse for which the drug is administered in a subject in need of suchtreatment. It is emphasized that a therapeutically effective amount ortherapeutic level of a drug will not always be effective in treating theconditions/diseases described herein, even though such dosage is deemedto be a therapeutically effective amount by those of skill in the art.For convenience only, exemplary dosages, drug delivery amounts,therapeutically effective amounts and therapeutic levels are providedbelow with reference to adult human subjects. Those skilled in the artcan adjust such amounts in accordance with standard practices as neededto treat a specific subject and/or condition/disease.

As used herein, “active surface area” means the surface area of thedrug-containing layer of the transdermal drug delivery system.

As used herein, “coat weight” refers to the weight of thedrug-containing layer per unit area of the active surface area of thetransdermal drug delivery system.

As used herein, “testosterone” includes androgenic steroids such astestosterone, testosterone acetate, testosterone enanthate, testosteroneproprionate, 17-beta-cypionate, testosterone nicotinate, testosteronephenylacetate, and non-esters that have groups on the 17 position, suchas testosterone 17-chloral hemiacetal.

As used herein, “flux” (also called “permeation rate”) is defined as theabsorption of a drug through skin or mucosal tissue, and is described byFick's first law of diffusion:

J=−D(dCm/dx)

where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm²/sec and dCm/dx is theconcentration gradient of the drug across the skin or mucosa.

As used herein, the term “transdermal” refers to delivery,administration or application of a drug by means of direct contact withskin or mucosa. Such delivery, administration or application is alsoknown as dermal, percutaneous, transmucosal and buccal. As used herein,“dermal” includes skin and mucosa, which includes oral, buccal, nasal,rectal and vaginal mucosa.

As used herein, “transdermal drug delivery system” refers to a system(e.g., a device) comprising a composition that releases testosteroneupon application to the skin (or any other surface noted above). Atransdermal drug delivery system may comprise a drug-containing layer,and, optionally, a backing layer and/or a release liner layer. In someembodiments, the transdermal drug delivery system is a substantiallynon-aqueous, solid form, capable of conforming to the surface with whichit comes into contact, and capable of maintaining such contact so as tofacilitate topical application without adverse physiological response,and without being appreciably decomposed by aqueous contact duringtopical application to a subject. Many such systems are known in the artand commercially available, such as transdermal drug delivery patches.As described below, in one embodiment, the transdermal drug deliverysystem comprises a drug-containing polymer matrix that comprises apressure-sensitive adhesive or bioadhesive, and is adopted for directapplication to a user's (e.g., a subject's) skin. In other embodiments,the polymer matrix is non-adhesive and may be provided with separateadhesion means (such as a separate adhesive layer) for application andadherence to the user's skin.

As used herein, “polymer matrix” refers to a polymer composition whichcontains one or more drugs. In some embodiments, the matrix comprises apressure-sensitive adhesive polymer or a bioadhesive polymer. In otherembodiments, the matrix does not comprise a pressure-sensitive adhesiveor bioadhesive. As used herein, a polymer is an “adhesive” if it has theproperties of an adhesive per se, or if it functions as an adhesive bythe addition of tackifiers, plasticizers, crosslinking agents or otheradditives. Thus, in some embodiments, the polymer matrix comprises apressure-sensitive adhesive polymer or a bioadhesive polymer, withtestosterone dissolved or dispersed therein. The polymer matrix also maycomprise tackifiers, plasticizers, crosslinking agents, enhancers,co-solvents, fillers, antioxidants, solubilizers, crystallizationinhibitors, or other additives described herein. U.S. Pat. No. 6,024,976describes polymer blends that are useful in accordance with thetransdermal systems described herein. The entire contents of U.S. Pat.No. 6,024,976 is incorporated herein by reference.

As used herein, the term “pressure-sensitive adhesive” refers to aviscoelastic material which adheres instantaneously to most substrateswith the application of very slight pressure and remains permanentlytacky. A polymer is a pressure-sensitive adhesive within the meaning ofthe term as used herein if it has the properties of a pressure-sensitiveadhesive per se or functions as a pressure-sensitive adhesive byadmixture with tackifiers, plasticizers or other additives.

The term pressure-sensitive adhesive also includes mixtures of differentpolymers and mixtures of polymers, such as polyisobutylenes (PIB), ofdifferent molecular weights, wherein each resultant mixture is apressure-sensitive adhesive. In the last case, the polymers of lowermolecular weight in the mixture are not considered to be “tackifiers,”said term being reserved for additives which differ other than inmolecular weight from the polymers to which they are added.

In some embodiments, the polymer matrix is a pressure-sensitive adhesiveat room temperature and has other desirable characteristics foradhesives used in the transdermal drug delivery art. Suchcharacteristics include good adherence to skin, ability to be peeled orotherwise removed without substantial trauma to the skin, retention oftack with aging, etc. In some embodiments, the polymer matrix has aglass transition temperature (T_(g)), measured using a differentialscanning calorimeter, of between about −70° C. and 0° C.

As used herein, the term “rubber-based pressure-sensitive adhesive”refers to a viscoelastic material which has the properties of apressure-sensitive adhesive and which contains at least one natural orsynthetic elastomeric polymer.

In some embodiments, the transdermal drug delivery system includes oneor more additional layers, such as one or more additional polymer matrixlayers, or one or more adhesive layers that adhere the transdermal drugdelivery system to the user's skin. In other embodiments, thetransdermal drug delivery system is monolithic, meaning that itcomprises a single polymer matrix layer comprising a pressure-sensitiveadhesive or bioadhesive with drug dissolved or dispersed therein, and norate-controlling membrane.

The transdermal drug delivery system also may include a drug impermeablebacking layer or film. In some embodiments, the backing layer isadjacent one face of the polymer matrix layer. When present, the backinglayer protects the polymer matrix layer (and any other layers present)from the environment and prevents loss of the drug and/or release ofother components to the environment during use. Materials suitable foruse as backing layers are well-known known in the art and can comprisefilms of polyester, polyethylene, vinyl acetate resins, ethylene/vinylacetate copolymers, polyvinyl chloride, polyurethane, and the like,metal foils, non-woven fabric, cloth and commercially availablelaminates. A typical backing material has a thickness in the range of 2to 1000 micrometers. For example, 3M's Scotch Pak™ 1012 or 9732 backingmaterial (a polyester film with an ethylene vinyl acetate copolymer heatseal layer) is useful in the transdermal drug delivery systems describedherein.

The transdermal drug delivery system also may include a release liner,typically located adjacent the opposite face of the system as comparedto the backing layer. When present, the release liner is removed fromthe system prior to use to expose the polymer matrix layer and/or anadhesive layer prior to topical application. Materials suitable for useas release liners are well-known known in the art and include thecommercially available products of Dow Corning Corporation designatedBio-Release® liner and Syl-off® 7610 (both silicone-based) and 3M's1020, 1022, 9744, 9748 and 9749 Scotchpak™ (fluoropolymer coatedpolyester films).

The transdermal drug delivery system may be packaged or provided in apackage, such as a pouchstock material used in the prior art fortransdermal drug delivery systems in general or for transdermaltestosterone drug delivery systems in particular. For example, DuPont'sSurlyn® can be used in a pouchstock material.

A used herein, a “monolithic” transdermal drug delivery system mayinclude a backing layer and/or release liner, and may be provided in apackage.

In accordance with some embodiments, the transdermal dug delivery systemcomprises a drug-containing polymer matrix layer that comprises apressure-sensitive adhesive blend comprising an acrylic polymer, asilicone polymer, and a soluble PVP.

Acrylic Polymers

The term “acrylic polymer” is used here as in the art interchangeablywith “polyacrylate,” “polyacrylic polymer,” and “acrylic adhesive.” Theacrylic-based polymers can be any of the homopolymers, copolymers,terpolymers, and the like of various acrylic acids or esters. In someembodiments, the acrylic-based polymers are adhesive polymers. In otherembodiments, the acrylic-based polymers function as an adhesive by theaddition of tackifiers, plasticizers, crosslinking agents or otheradditives.

The acrylic polymer can include copolymers, terpolymers andmultipolymers. For example, the acrylic polymer can be any of thehomopolymers, copolymers, terpolymers, and the like of various acrylicacids. In some embodiments, the acrylic polymer constitutes from about2% to about 95% by weight of the polymer content of the polymer matrix,including about 3% to about 90% and about 5% to about 85%, such as 2% to95%, 3% to 90% and 5% to 85%. In some embodiments, the amount and typeof acrylic polymer is dependent on the type and amount of testosteroneused.

Acrylic polymers useful in practicing the invention include polymers ofone or more monomers of acrylic acids and other copolymerizablemonomers. The acrylic polymers also include copolymers of alkylacrylates and/or methacrylates and/or copolymerizable secondary monomersor monomers with functional groups. Combinations of acrylic-basedpolymers based on their functional groups is also contemplated.Acrylic-based polymers having functional groups include copolymers andterpolymers which contain, in addition to nonfunctional monomer units,further monomer units having free functional groups. The monomers can bemonofunctional or polyfunctional. By varying the amount of each type ofmonomer added, the cohesive properties of the resulting acrylic polymercan be changed as is known in the art. In some embodiments, the acrylicpolymer is composed of at least 50% by weight of an acrylate or alkylacrylate monomer, from 0 to 20% of a functional monomer copolymerizablewith the acrylate, and from 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid and methacrylicacid and alkyl acrylic or methacrylic esters such as methyl acrylate,ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, methyl methacrylate, hexyl methacrylate,heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, glycidyl acrylate, and corresponding methacrylicesters.

Non-functional acrylic-based polymers can include any acrylic basedpolymer having no or substantially no free functional groups.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

As used herein, “functional monomers or groups,” are monomer unitstypically in acrylic-based polymers which have reactive chemical groupswhich modify the acrylic-based polymers directly or which provide sitesfor further reactions. Examples of functional groups include carboxyl,epoxy, hydroxyl, sulfoxyl, and amino groups. Acrylic-based polymershaving functional groups contain, in addition to the nonfunctionalmonomer units described above, further monomer units having freefunctional groups. The monomers can be monofunctional or polyfunctional.These functional groups include carboxyl groups, hydroxy groups, aminogroups, amido groups, epoxy groups, etc. Typical carboxyl functionalmonomers include acrylic acid, methacrylic acid, itaconic acid, maleicacid, and crotonic acid. Typical hydroxy functional monomers include2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethylacrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropylmethacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,hydroxyhexyl methacrylate. As noted above, in some embodiments, theacrylic polymer does not include such functional groups.

Further details and examples of acrylic adhesives which are suitable inthe practice of the invention are described in Satas, “AcrylicAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed.,pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989);“Acrylic and Methacrylic Ester Polymers,” Polymer Science andEngineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons, (1984);U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267, all of which areexpressly incorporated by reference in their entireties.

Suitable acrylic polymers also include pressure-sensitive adhesiveswhich are commercially available, such as the acrylic-based adhesivessold under the trademarks DURO-TAK® by National Starch and ChemicalCorporation, Bridgewater, N.J. (such as DURO-TAK® 87-2287, -4098, -2852,-2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085, -9088 and73-9301). Other suitable acrylic adhesives include those sold under thetrademark EUDRAGIT® by Roehm Pharma GmbH, Darmstadt, Germany, those soldby Cytec Surface Specialties, St. Louis, Mo., under the trademarksGELVA® Multipolymer Solution (such as GELVA® 2480, 788, 737, 263, 1430,1753, 1151, 2450, 2495, 3067, 3071, 3087 and 3235). For example, hydroxyfunctional adhesives with a reactive functional OH group in thepolymeric chain, can be used. Non-limiting commercial examples of thistype of adhesives include both GELVA® 737, 788, and 1151, and DURO-TAK®87-2287, -4287, -2510 and -2516.

Silicon Polymers

The term “silicone-based” polymer is used interchangeably with the termssilicon polymers, siloxane, polysiloxane, and silicones as used hereinand as known in the art. A suitable silicone-based polymer may also be apressure-sensitive adhesive. Thus, in some embodiments, thesilicone-based polymer is an adhesive polymer. In other embodiments, thesilicone-based polymer functions as an adhesive by the addition oftackifiers, plasticizers, crosslinking agents, or other additives.

Suitable polysiloxanes include silicone pressure-sensitive adhesiveswhich are based on two major components: (i) a polymer or gum and (ii) atackifying resin. A polysiloxane adhesive can be prepared bycross-linking a gum, typically a high molecular weightpolydiorganosiloxane, with a resin, to produce a three-dimensionalsilicate structure, via a condensation reaction in an appropriateorganic, volatile solvent, such as ethyl acetate or heptane. The ratioof resin to polymer can be adjusted in order to modify the physicalproperties of polysiloxane adhesives. Sobieski, et al., “SiliconePressure Sensitive Adhesives,” Handbook of Pressure-Sensitive AdhesiveTechnology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold,New York (1989).

Exemplary silicone-based polymers are adhesives (e.g., capable ofsticking to the site of topical application), includingpressure-sensitive adhesives. Illustrative examples of silicone-basedpolymers having reduced silanol concentrations include silicone-basedadhesives (and capped polysiloxane adhesives) such as those described inU.S. Pat. No. Re. 35,474 and U.S. Pat. No. 6,337,086, which areincorporated herein by reference in their entireties, and which arecommercially available from Dow Corning Corporation (Dow CorningCorporation, Medical Products, Midland, Mich.) as BIO-PSA® 7-4100, -4200and -4300 product series, and non-sensitizing, pressure-sensitiveadhesives produced with compatible organic volatile solvents (such asethyl acetate or heptane) and available commercially under theirBIO-PSA® 7-4400 series, -4500 series, such as -4502, and -4600 series.

Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the polymer matrices and compositions and methodsdescribed herein are mentioned in the following U.S. Pat. Nos.4,591,622; 4,584,355; 4,585,836; and 4,655,767, which are all expresslyincorporated by reference herein in their entireties. It should also beunderstood that silicone fluids are also contemplated for use in thepolymer matrices and methods described herein.

In some embodiments, the polysiloxane constitutes from about 9% to about97% of the polymer content of the polymer matrix, including about 8% toabout 97% and about 14% to about 94%, such as 9% to 97%, 8% to 97%, and14% to 94%.

Soluble PVP

In some embodiments, the polymer matrix includes soluble PVP. SolublePVP has been found to be highly effective in preventing crystallizationof drugs, such as testosterone, in adhesive-type transdermal drugdelivery system. Soluble PVP also may modulate the transdermalpermeation rate of the drug.

The term “PVP” or “polyvinylpyrrolidone” refers to a polymer, either ahomopolymer or copolymer, containing N-vinylpyrrolidone as the monomericunit. Typical PVP polymers are homopolymeric PVPs and the copolymervinyl acetate vinylpyrrolidone. The homopolymeric PVPs are known to thepharmaceutical industry under a variety of designations includingPovidone, Polyvidone, Polyvidonum, Polyvidonum soluble, andPoly(l-vinyl-2-pyrrolidone). The copolymer vinyl acetatevinylpyrrolidone is known to the pharmaceutical industry as Copolyvidon,Copolyvidone, and Copolyvidonum. The term “soluble” when used withreference to PVP means that the polymer is soluble in water andgenerally is not substantially cross-linked, and has a molecular weightof less than about 2,000,000. See, generally, Buhler, KOLLIDON®:POLYVINYLPRYRROLIDONE FOR THE PHARMACEUTICAL INDUSTRY, BASFAktiengesellschaft (1992).

The amount and type of soluble PVP used may depend on the quantity andtype of testosterone present, as well as the type of adhesive, but canbe readily determined through routine experimentation. Typically, thePVP is present in an amount from about 1% to about 20% by weight,preferably from about 5% to about 15% by weight, based on the totalweight of the polymer matrix. However, the amount of PVP can be higherthan 20% for example, up to 40%, depending on the particular drug usedand on the desired properties of the blend. The soluble PVP may have amolecular weight of about 2,000 to 1,100,000, including 5,000 to100,000, and 7,000 to 54,000. In some embodiments, the soluble PVP has amolecular weight of from about 17,000 to about 90,000, such as fromabout 17,000 to about 60,000, including from 17,000 to 90,000 and from17,000 to 60,000.

In some embodiments, the polymer matrix comprises a soluble PVP with arubber-based pressure-sensitive adhesive and a polyacrylate polymer,such as a blend of an acrylic polymer, a polysiloxane and a soluble PVP.In some embodiments, the blend is chosen to affect the rate of drugdelivery. More specifically, a plurality of polymers including a solublepolyvinylpyrrolidone, which may have different solubility parameters forthe drug and which may be immiscible with each other, may be selected toadjust the solubility of the drug in the polymer matrix, therebycontrolling the maximum concentration of the drug in the system, andmodulating drug delivery through the dermis.

The amount of acrylic-based polymer and silicone-based polymer can beadjusted so as to modify the saturation concentration of the drug in thepolymer matrix in order to affect the rate of delivery of the drug fromthe system and through the skin. In some embodiments, the acrylic-basedpolymer and silicone-based polymer are used in a weight ratio of fromabout 2:98 to about 96:4, including about 2:98 to about 90:10 and 2:98to about 86:14, such as 2:98 to 96:4, 2:98 to 90:10 and 2:98 to 86:14.

The concentration by weight of the testosterone in the transdermal drugdelivery system is typically about 0.1 to about 50%, including about 0.1to about 40% and about 0.3 to about 30%, such as 0.1 to 50%, 0.1 to 40%and 0.3 to 30%, all based on the total weight of the polymer matrix. Insome embodiments, the testosterone is testosterone, and is present at anamount of from about 0.1 to 10%, including from about 0.1 to about 5%,such as from 0.1 to 10% and 0.1 to 5%, all based on the total dry weightof the polymer matrix. Irrespective of whether there is high-loading orlow-loading of the testosterone into the transdermal drug deliverysystem, the pressure-sensitive adhesive composition can be formulated tomaintain acceptable shear, tack, and peel adhesive properties.

Stabilizers

In some embodiments, the polymer matrix comprises a stabilizer thatstabilizes the testosterone. For example, testosterone can be formulatedwith an antioxidant such as butylhydroxytoluene (BHT),butylhydroxyanisole (BHA), ascorbyl palmitate, alpha-tocopherol and itsesters, citric acid and propyl gallate, and mixtures thereof. In someembodiments, a stabilizer may be used in an amount of about 0.001 toabout 0.1% by weight, including about 0.01% by weight, such as 0.01% byweight, based on the dry weight of the polymer matrix.

Other Components

In one embodiment, the polymer matrix comprises a penetration enhancer.A “penetration enhancer” is an agent known to accelerate the delivery ofthe drug through the skin. These agents also have been referred to asaccelerants, adjuvants, and sorption promoters, and are collectivelyreferred to herein as “enhancers.” This class of agents includes thosewith diverse mechanisms of action, including those which have thefunction of improving percutaneous absorption, for example, by changingthe ability of the stratum corneum to retain moisture, softening theskin, improving the skin's permeability, acting as penetrationassistants or hair-follicle openers or changing the state of the skinincluding the boundary layer.

Illustrative penetration enhancers include but are not limited topolyhydric alcohols such as dipropylene glycol, propylene glycol, andpolyethylene glycol; oils such as olive oil, squalene, and lanolin;fatty ethers such as cetyl ether and oleyl ether; fatty acid esters suchas isopropyl myristate; urea and urea derivatives such as allantoinwhich affect the ability of keratin to retain moisture; polar solventssuch as dimethyidecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered. Other agents include oleic andlinoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, andisopropyl palmitate.

In one embodiment, the penetration enhancer is oleyl alcohol. In anotherembodiment, the penetration enhancer is a glycol, such as dipropyleneglycol, propylene glycol, butylene glycol or polyethylene glycol. Inother embodiments, the penetration enhancer comprises a mixture of atleast two penetration enhancers. For example, a penetration enhancer maycomprise oleyl alcohol and one or more polyhydric alcohols, such asglycerine, dipropylene glycol, butylene glycol, propylene glycol. Forinstance, the penetration enhancer may include oleyl alcohol anddipropylene glycol.

In some embodiments, a penetration enhancer is used in an amount up toabout 30% by dry weight of the polymer matrix, including up to 30% byweight, up to about 20% by weight, including 20% by weight, or up toabout 10% by weight, up to 10% by weight, or up to 5% by weight,including up to 5% by weight, based on the dry weight of the polymermatrix. In some embodiments, a penetration enhancer is used in an amountof from about 5% to about 15%, such as from 5% to 15%. In specificembodiments, the penetration enhancer comprises a mixture of oleylalcohol and dipropylene glycol which together amount to about 14% byweight of the polymer matrix. The polymer matrix may further comprisevarious thickeners, fillers, and other additives or components known foruse in transdermal drug delivery systems.

The amount of testosterone to be incorporated in the polymer matrixvaries depending on the particular drug, the desired therapeutic effect,and the time span for which the system is to provide therapy. For mostdrugs, the passage of the drugs through the skin will be therate-limiting step in delivery. A minimum amount of drug in the systemis selected based on the amount of drug which passes through the skin inthe time span for which the system is to provide therapy. In someembodiments, a system for the transdermal delivery of testosterone isused over a period of about 1 day, about 3 days, about 7 days, orlonger. Thus, in one embodiment, the systems comprise an amount of drug(e.g., testosterone) sufficient to deliver therapeutically effectiveamounts of drug over a period of from 1 day to 3 days, 7 days, orlonger, including for 1 day, for 2 days, for 3 days, for 4 days, for 5days, for 6 days, for 7 days, or for longer.

In some embodiments, a therapeutically effective amount of testosteronedelivered by the composition is from about 100 to about 500 μg/day,including 100-500 μg/day and 100-450 μg/day, and further including atleast about 300 μg/day, including 300 μg/day. Thus, in some embodiments,the transdermal drug delivery system comprises an amount of testosteroneeffective to achieve a delivery of from about 100 to about 500 μg/day,including 100-500 μg/day or 100-450 μg/day, or at least about 300μg/day, including 300 μg/day. As noted above, in some embodiments, theserates are achieved over a duration of application of at least about 1day, including at least about 3 days and at least about 7 days, such asat least 1 day, at least 2 days, at least 3 days, at least 4 days, atleast 5 days, at least 6 days, and at least 7 days.

In some embodiments, the transdermal drug delivery system comprises asmaller amount of testosterone than an Intrinsa® product, but achievescomparable drug delivery. For example, in some embodiments a transdermaldrug delivery system according to the invention may contain about 4 mg,including 3.94 mg, testosterone in a 14 cm² device, and achieve drugdelivery comparable to an Intrinsa® product that contains about 8 mg,including 8.4 mg, testosterone in a 28 cm² device.

In some embodiments, the system comprises a polymer matrix comprising anamount of acrylic-based polymer of about 1 to about 70% by weight,including about 2 to about 25% by weight, based on the dry weight of thepolymer matrix, such as 2-25% by weight acrylic-based polymer.

In some embodiments, the system comprises a polymer matrix comprising anamount of silicone polymer of about 5 to about 70% by weight, includingabout 45 to about 70% by weight, based on the dry weight of the polymermatrix, such as 45-70% by weight silicone polymer.

In some embodiments, the system comprises a polymer matrix comprising anamount of soluble PVP of about 1 to about 30% by weight, including about2 to about 25% by weight, based on the dry weight of the polymer matrix,such as 2-25% by weight soluble PVP.

In some embodiments, the system comprises a polymer matrix comprising anamount of oleyl alcohol of about 1 to about 10% by weight, includingabout 4 to about 8% by weight, based on the dry weight of the polymermatrix, such as 4-8% by weight oleyl alcohol.

In some embodiments, the system comprises a polymer matrix comprising anamount of dipropylene glycol of about 1 to about 10% by weight,including about 5 to about 10% by weight, based on the dry weight of thepolymer matrix, such as 5-10% by weight dipropylene glycol.

In some embodiments, the system comprises a polymer matrix comprising anamount of an antioxidant, such as butylhydroxytoluene (BHT), of about0.001 to about 0.1% by weight, including about 0.01% by weight, based onthe dry weight of the polymer matrix, such as 0.01% by weightbutylhydroxytoluene (BHT).

In some embodiments, the polymer matrix comprises about 2-25% by weightacrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25%by weight soluble PVP, about 0-15% penetration enhancer, and about0.1-10% by weight testosterone, and, optionally, about 0.001 to about0.1% by weight butylhydroxytoluene (BHT), all based on the dry weight ofthe polymer matrix. In specific embodiments, the polymer matrixcomprises about 20% by weight acrylic adhesive, about 59% by weightsilicone adhesive, about 12% by weight soluble PVP, about 6% by weightoleyl alcohol, about 2-3% by weight testosterone and, optionally, about0.01% by weight butylhydroxytoluene (BHT).

In some embodiments, the acrylic adhesive and silicone adhesive arepresent in a ratio of from about 1:2 up to less than about 1:7, such asup to about 1:6, based on the weight of the acrylic and siliconeadhesives. For example, in some embodiments, the acrylic adhesive andsilicone adhesive are present in a ratio of about 1:2, 1:3, 1:4, 1:5 or1:6, based on the weight of the acrylic and silicone adhesives. Inspecific embodiments, the acrylic adhesive and silicone adhesive arepresent in a ratio of 1:2.8, based on the weight of the acrylic andsilicone adhesives.

As noted above, in embodiments where the polymer matrix comprises apressure-sensitive adhesive or bioadhesive, the polymer matrix can serveas an adhesive portion of the system (e.g., a reservoir device), or canserve as one or more layers of a multi-layer system. Alternatively, apolymer matrix comprising a pressure-sensitive adhesive or bioadhesivewith drug dissolved or dispersed therein can constitute a monolithicdevice. In embodiments where the polymer matrix does not comprise anadhesive, but instead, for example, comprises a polymeric drugreservoir, it can be used in combination with one or more adhesivelayers, or with a surrounding adhesive portion, as is well known tothose skilled in the art.

In some embodiments, the system consists essentially of the polymermatrix layer. By “consists essentially of the polymer matrix layer”means that the system does not contain any other layers that affect drugdelivery, such as an additional rate-controlling polymer layer,rate-controlling membrane, or drug reservoir layer. It will beunderstood, however, that the system that consists essentially of thepolymer matrix layer may comprise a backing layer and/or release liner.

As discussed above, in some embodiments, the systems have a greater fluxthan other known testosterone devices for use by females (such asIntrinsa®, manufactured by Watson Pharmaceuticals Inc.), and, therefore,exhibit increased drug delivery per unit area of the active surfacearea. For example, in some embodiments, the systems exhibit a fluxgreater than the about 0.45 μg/cm²/hour exhibited by the Intrinsa®product, such as a flux that is about double, such as a flux of about0.89 μg/cm²/hour. In some embodiments, the systems described hereinachieve a flux that is at least about 0.7 μg/cm²/hour, including atleast 0.7 μg/cm²/hour, including at least about 0.89 μg/cm²/hour and atleast 0.89 μg/cm²/hour, or at least about 1.0 μg/cm²/hour, including atleast 1.0 μg/cm²/hour, over a period of time of at least about 1 day,including at least about 3 days and at least about 7 days, such as atleast 1 day, at least 2 days, at least 3 days, at least 4 days, at least5 days, at least 6 days, and at least 7 days.

In some embodiments, the systems have a different coat weight than otherknown testosterone devices. In some embodiments, the polymer matrix hasa coat weight of greater than about 10 mg/cm². In some embodiments, thepolymer matrix has a coat weight selected from the group consisting ofabout 12.0, about 12.5, about 13.0 and about 15 mg/cm².

In some embodiments, the systems have an amount of testosterone per unitarea of the active surface area that is less than the 0.3 mg/cm²testosterone of the Intrinsa® product, such as an amount of testosteroneof about 0.28 mg/cm².

The system may be of any shape or size suitable for transdermalapplication. In some embodiments, the systems are smaller than theIntrinsa® product, but achieve comparable daily dosages. For example,the systems may have an active surface area of 50% of the active surfacearea of an Intrinsa product, such as about 50% of 28 cm², and deliver adaily dosage of testosterone comparable to that of the Intrinsa®product, such as an amount of testosterone of at least about 300 μg/day.In one embodiment, the system has an active surface area of about 14 cm²and delivers a daily dosage of testosterone comparable to that of the 28cm² Intrinsa® product, e.g., about 300 μg/day.

The polymer matrices described herein may be prepared by methods knownin the art. The polymer matrices can be formed into systems by methodsknown in the art. For example, the polymer matrix material can beapplied to a backing layer and release liner by methods known in theart, and formed into sizes and shapes suitable for use.

For example, after the polymer matrix is formed, it may be brought intocontact with a support layer, such a releaser liner layer or backinglayer, in any manner known to those of skill in the art. Such techniquesinclude calender coating, hot melt coating, solution coating, etc.

For example, a polymer matrix can be prepared by blending the componentsof the polymer matrix, applying the matrix material to a support layersuch as a backing layer or release liner, and removing any remainingsolvents. The testosterone can be added at any stage. In one embodiment,all polymer matrix components, including testosterone, are blendedtogether. In another embodiment, the polymer matrix components otherthan testosterone are blended together, and then the testosterone isdissolved or dispersed therein. The order of steps, amount ofingredients, and the amount and time of agitation or mixing can bedetermined and optimized by the skilled practitioner. An exemplarygeneral method is as follows:

Appropriate amounts of soluble PVP, solvent(s), enhancer(s), and organicsolvent(s) (for example toluene, or ethyl acetate an/or isopropylalcohol) are combined and thoroughly mixed together in a vessel.

Testosterone and any antioxidant being used (such as BHT) are added tothe mixture and agitation is carried out until the drug is uniformlymixed in.

Appropriate amounts of polysiloxane and acrylic polymer are then addedto the drug mixture, and thoroughly mixed.

The formulation is then transferred to a coating operation where it iscoated onto a protective release liner at a controlled specifiedthickness. The coated product is then passed through an oven in order todrive off all volatile processing solvents.

The dried product on the release liner is then joined to the backingmaterial and wound into rolls for storage.

Appropriate size and shape “systems” are die-cut from the roll materialand then pouched.

Other manufacturing methods are known in the art that are suitable formaking the systems described herein.

In some embodiments, there is provided a method of effecting transdermaldrug delivery of testosterone, such as testosterone, by applying asystem as described herein to the skin or mucosa of a subject in needthereof. In some embodiments, the system comprises testosterone, and thesystem is applied over a period of at least about 1 day, at least about2 days, at least about 3 days, at least about 4 days, at least about 5days, at least about 6 days, or at least about 7 days, such as for 1, 2,3, 4, 5, 6 or 7 days. In some embodiments, the method is effective toachieve therapeutic levels of testosterone in the subject during theapplication period. As noted above, a typical testosterone dosage rangesfrom at least about 100 to about 500 μg/day, including 100-500 μg/dayand 100-450 μg/day, including at least about 300 μg/day, including 300μg/day.

In some embodiments, the systems described herein are designed for useby female patients, including female patients undergoing testosteronetherapy for congestive heart failure. In other embodiments, the systemsdescribed herein are designed for use by female patients undergoinghormone replacement therapy or therapy to improve their libido. In someembodiments, the systems described herein may be designed are adaptedfor use by male patients.

The following specific examples are included as illustrative of thetransdermal drug delivery systems and polymer matrices described herein.These example are in no way intended to limit the scope of theinvention. Other aspects of the invention will be apparent to thoseskilled in the art to which the invention pertains.

Example 1

A polymer matrix with the following composition is prepared:

% w/w in Finished Ingredient Dry Product Silicone polymer 59.74 (BIO PSA4502) Acrylic polymer (Gelva 788) 20.00 PVP (Povidone 30) 12.00 OleylAlcohol 6.00 Butylated Hydroxytoluene 0.01 Testosterone USP, CIII 2.25Total 100.00

The polymer matrix is applied with a coat weight of 12.5 mg/cm² to aScotch Pak™ 1022 release liner, and Scotch Pak™ 9732 (polyethylene)backing material is applied. Individual systems with an active surfacearea of 14 cm² are prepared. The systems are packaged in Surlyn® 0.0007pouchstock material.

Human cadaver skin permeation studies are performed to quantitativelydetermine the effective permeation through the stratum corneum. Thestratum corneum is obtained from split thickness, cryo-preserved cadaverskin by the heat separation technique. Samples of 5/16″ diameter are cutfrom the laminate, in quadruplicate, and mounted onto ½″ cut pieces ofthe stratum corneum. These samples are place on modified Franz diffusioncells. The receptor is filled with 7.5 mL of 0.9% NaCl and 0.01% NaN₃ indeionized water. The cells are maintained at a constant 32° C. andmagnetically stirred at approximately 300 rpm. At specified time points,samples of the receptor phase are taken with complete replacement of thereceptor phase. These samples are quantified by high-performance liquidchromatography (HPLC) utilizing Waters HPLC instrumentation. C-8 (15cm×4.6 mm) 5 μm particle size columns (HYPERSIL made by MetaChemTechnologies, Inc., Torrance, Calif.) are used at 50° C. (columntemperature).

FIG. 1 illustrates the testosterone flux (μg/cm²/hr) over time (0-96hours) from a transdermal delivery system according to the invention (,top line), as compared to Intrinsa® (♦, bottom line).

FIG. 2 illustrates the cumulative amount of drug delivered per unit area(μg/cm²) over time (0-96 hours) from a transdermal delivery systemaccording to the invention (, top line), as compared to Intrinsa® (♦,bottom line).

The results show that the system according to the invention achieves agreater flux than the Intrinsa® product and is able to achievetherapeutic daily dosages (such as at least 300 μg/day over three tofour days) despite its significantly smaller size.

1. A transdermal drug delivery system comprising a drug-containing layerdefining an active surface area and comprising a polymer matrixcomprising 2-25% by weight acrylic adhesive, 45-70% by weight siliconeadhesive, about 2-25% by weight soluble polyvinylpyrrolidone (PVP),about 5-15% penetration enhancer, and about 0.1-10% by weighttestosterone, all based on the total dry weight of the polymer matrix,wherein the system includes less than 0.3 mg/cm² testosterone, andachieves a testosterone flux that is at least 0.7 μg/cm²/hour, based onthe active surface area.
 2. The transdermal drug delivery system ofclaim 1, wherein the system achieves a testosterone flux that is atleast 0.89 μg/cm²/hour, based on the active surface area. 3-4.(canceled)
 5. The transdermal drug delivery system of claim 1, whereinthe penetration enhancer comprises oleyl alcohol.
 6. The transdermaldrug delivery system of claim 1, wherein the composition furthercomprises an antioxidant selected from the group consisting ofbutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbylpalmitate, alpha-tocopherol and its esters, citric acid and propylgallate, and mixtures thereof.
 7. The transdermal drug delivery systemof claim 6, wherein the antioxidant comprises BHT.
 8. The transdermaldrug delivery system of claim 1, wherein the acrylic adhesive andsilicone adhesive are present in a ratio of from about 1:2 to about 1:6,based on the total weight of the acrylic and silicone adhesives.
 9. Thetransdermal drug delivery system of claim 1, wherein the polymer matrixcomprises an amount of testosterone effective to deliver atherapeutically effective amount of testosterone over a period of timeselected from the group consisting of at least 1 day, at least 2 days,at least 3 days, at least 4 days, at least 5 days, at least 6 days andat least 7 days.
 10. The transdermal drug delivery system of claim 1,wherein the polymer matrix comprises an amount of testosterone effectiveto deliver an amount of testosterone of from about 100 to about 500μg/day.
 11. The transdermal drug delivery system of claim 1, wherein thepolymer matrix comprises an amount of testosterone effective to deliveran amount of testosterone of from about 100 to about 450 μg/day.
 12. Thetransdermal drug delivery system of claim 1, wherein the polymer matrixcomprises an amount of testosterone effective to deliver an amount oftestosterone of from about 300 μg/day to about 500 μg/day. 13-14.(canceled)
 15. The transdermal drug delivery system of claim 1, whereinthe polymer matrix has a coat weight of greater than about 10 mg/cm².16. The transdermal drug delivery system of claim 1, wherein the polymermatrix has a coat weight of about 12.5 mg/cm².
 17. A transdermal drugdelivery system comprising a polymer matrix comprising 2-25% by weightacrylic adhesive, 45-70% by weight silicone adhesive, about 2-25% byweight soluble PVP, about 5-15% penetration enhancer, and about 0.1-10%by weight testosterone, all based on the total dry weight of the polymermatrix, wherein the system has an active surface area of 14.0 cm² and iseffective to deliver an amount of testosterone per day of from about 300μg to about 500 μg.
 18. A method for administering testosterone,comprising applying to the skin or mucosa of a subject in need thereof atransdermal drug delivery system comprising a drug-containing layerdefining an active surface area and comprising a polymer matrixcomprising 2-25% by weight acrylic adhesive, 45-70% by weight siliconeadhesive, about 2-25% by weight soluble PVP, about 5-15% penetrationenhancer, and about 0.1-10% by weight testosterone, all based on thetotal dry weight of the polymer matrix, wherein the system includes lessthan 0.3 mg/cm² testosterone, and achieves an testosterone flux that isat least 0.7 μg/cm²/hour, based on the active surface area.
 19. Themethod of claim 18, wherein the system achieves a testosterone flux thatis at least 0.89 μg/cm²/hour, based on the active surface area.
 20. Themethod of claim 18, wherein the system has an active surface area thatis about 14.0 cm² and is effective to deliver an amount of testosteroneper day of from about 300 μg to about 500 μg.
 21. A method of making atransdermal drug delivery system for administering testosterone,comprising forming a polymer matrix comprising about 0.1-10% by weighttestosterone and a polymer blend comprising 2-25% by weight of anacrylic adhesive, 45-70% by weight of a silicone adhesive, about 5-15%by weight of a penetration enhancer, and about 2-25% by weight solublePVP, all based on the total dry weight of the polymer matrix, andapplying the polymer matrix to a support layer such that the systemincludes less than 0.3 mg/cm² testosterone.
 22. The method of claim 21,wherein the system has an active surface area that is about 14.0 cm².23. (canceled)
 24. The method of claim 21, wherein the polymer matrixfurther comprises about 0.01% by weight BHT, based on the total dryweight of the polymer matrix.
 25. The method of claim 21, wherein thepolymer matrix is applied to the support layer at a coat weight ofgreater than about 10 mg/cm².
 26. The method of claim 21, wherein thepolymer matrix coat weight is about 12.5 cm².